For quite some time chemical compounds having immunomodulatory effects are known in the art. To these compounds also belongs 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt. This compound is known from EP 1 203 587 A and has the following basic structure (Na+ not shown):

The above basic structure is also called luminol. Other common synonymous terms are 3-aminophthalhydrazide, 3-aminophthalic hydrazide, o-aminophthalhydrazide and o-aminophthalic hydrazide. It is known from prior art that 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts crystallize as solids in different hydrate forms. In prior art, in particular the dihydrate of the sodium salt (RU2113222C1) and a trihydrate of the potassium salt and mixed forms thereof (RU2211036C2) are described. In addition, crystal structures of 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts partially differing in their hydration stage are known from scientific literature. A structural characterization is provided for a potassium salt anhydrate, a lithium salt monohydrate, a rubidium salt dihydrate, a caesium salt trihydrate and a sodium salt hexahydrate (cf. Guzei et al. (2013): Journal of Coordination Chemistry, 66:21, 3722-3739). Also a dihydrate as well as two polymorphic anhydrates of the sodium salt have been characterized structurally. The characterization was conducted from mixtures containing either both of said anhydrate forms or all three forms (cf. Rybakov et al. (2014): Crystallography Reports, 59, 383-393).
Pure crystalline forms of 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt anhydrate were first described in WO2011/107295A1 as form I and form II. The crystalline forms disclosed in WO2011/107295A1 were characterized by a X-ray powder diffractogram, expressed in D or 2-theta values, whereas “D” represents interplanar spacings and “2-theta” represents the 2-theta angles in degrees. The interplanar spacing D (also d) describes the vertical distance between two consecutive lattice planes. The Bragg angle theta (θ) indicates the characteristic angle resulting of the reflection of the incident X-ray beam at a lattice layer of the crystal, thereby producing a X-ray diffraction pattern. Both parameters are linked via the Bragg formula:nλ=2d sin(θ).By these characteristic values d and θ a crystal is characterized necessarily and sufficiently.
D-values were disclosed in WO2011/107295A1 with
13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1 and 3.0 for form I; and with
12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3 and 3.2 for form II.
2-theta-angles were disclosed with
6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7 and 30.3 for form I; and with
6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2 and 27.8 for form II.
In addition, the relative intensities of the reflections were reported.
WO2011/107295A1 also lists a number of rather complex methods of production for both form I as well as form II.
It is known in the art that crystalline forms of a substance can differ in their physical properties such as solubility, dissolution rate, and stability (cf. Haleblian und McCrone (1969): Journal of Pharmaceutical Sciences, 58:911-929). Such properties can affect the pharmaceutical processing of the active ingredient as well as its biological availability and pharmacokinetics, and thus its biological efficacy (cf. Griesser (2006) in: Polymorphisms in the Pharmaceutical Industry. Hilfiker (Ed.) 211-234). For the production of medicines it is important that the starting material is stable, not hygroscopic and controllable in its behavior as a solid during the complete production process. Further, the chemical stability and solid-phase stability (phase purity) with long storability of an active ingredient is extremely important (cf. Miller et al. (2006) in: Polymorphisms in the Pharmaceutical Industry. Hilfiker (Ed.) 385-403). It is desirable that even over a longest possible storing time the physical properties of the active ingredient will be maintained. This relates e.g. to the hygroscopicity, solubility or initial dissolution rate of the active ingredient, but also to phase purity.
Very important for the pharmaceutical processing and the medical use are production methods which reliably and reproducibly permit the production of the desired crystalline forms. When producing crystalline forms, it should be considered that even small deviations of the process parameters will cause changes of the crystal structure of the products and can thus finally lead to different crystalline forms or mixed forms. Properties changed thereby—for instance a modified biological efficacy by a different solubility—may lead to a rejection of complete batches. Often it is not possible at all to produce the desired form (cf. Ulrich und Jones (2005): Nachrichten aus der Chemie 53:19-23). Besides phase purity of the active ingredient and the resulting possible changes in the efficacy further important properties for the pharmaceutical processing can be affected in an adverse manner, e.g. the capability to be pressed to tablets by an impairment of the pourability or of the flow rate of the crystalline form.
5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts belong to the group of aminophthalhydrazides and are described in prior art as immunomodulators with specific anti-inflammatory, antioxidative and antitoxic properties (cf. WO2011/107295A1, U.S. Pat. No. 6,489,326B1; EP0617024B1, U.S. Pat. No. 5,512,573A, U.S. Pat. No. 5,543,410A, U.S. Pat. No. 7,326,690B2).
Immunomodulatory substances are commonly classified according to their effects into immunosuppressants and immunostimulants (cf. Rote Liste Service GmbH (2014): www.rote-liste.de, access on Sep. 2, 2014). The corresponding preparations with an exclusively immunosuppressive or an exclusively immunostimulatory effect, such as immunosuppressive TNF alpha blockers or immunostimulatory interferon beta preparations, often cause significant undesired side effects in the organism, actually because of their very specific mode of action. Some known immunosuppressive substances, such as the TNF alpha blocker adalimumab, specifically inhibit certain inflammatory mediators. Such therapies are known to have serious side effects (cf. Descotes (2008): Expert Opin. Drug Metab. Toxicol., 4:12:1537-1549), since the blocking of individual inflammatory mediators is a severe intervention into the complex immune system. For instance, in the case of adalimumab opportunistic infections such as sepsis occur frequently, occasionally malign lymphoma can occur as well. Consequently the organism is not capable anymore to fulfil its functions, hence reacting automatically and physiologically in an appropriate manner to exogenous and endogenous inflammatory stimuli such as bacterial infections. Thus, for instance, the application of TNF alpha blockers is contraindicated in the case of serious infections, this applies in particular for sepsis and tuberculosis. Before administering a corresponding medication, e.g. for the treatment of rheumatoid arthritis, a TBC screening is strongly recommended. Moreover, Hoffmann (2005: Intensivmed 42:371-377) could clearly demonstrate that TNF alpha blockers are not suitable for the clinical application in case of septic conditions, but to the contrary may even lead to an increased mortality.
The particular pharmacologic properties of the 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts are, however, very useful, a.o. for the prevention of so-called cytokine storms caused by excessive immune responses. In contrast to the so-called cytokine blockers these salts are mostly free of side effects since an inhibition of individual cytokines will not take place, but these are regulated to a physiological level, and thus an adequate reaction of the organism to infectious pathogens is assured further on. Correctly speaking, the term to use in this case should be immunoregulators instead of immunomodulators.